title: Lysosomal network proteins as potential novel CSF biomarkers for Alzheimer's disease.
abstract: The success of future intervention strategies for Alzheimer's disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.
authors.affiliation: Experimental Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden, andrea.armstrong@liu.se.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armstrong
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.forename: Hanna
authors.initials: H
authors.lastname: Appelqvist
authors.forename: Camilla
authors.initials: C
authors.lastname: Janefjord
authors.forename: Linnea
authors.initials: L
authors.lastname: Sandin
authors.forename: Lotta
authors.initials: L
authors.lastname: Agholme
authors.forename: Bob
authors.initials: B
authors.lastname: Olsson
authors.forename: Samuel
authors.initials: S
authors.lastname: Svensson
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Katarina
authors.initials: K
authors.lastname: Kågedal
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000134:cerebrospinal fluid; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001343:Autophagy; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002556:Cerebrospinal Fluid Proteins / Q000134:cerebrospinal fluid*; D011992:Endosomes / Q000737:chemistry; D005260:Female; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000134:cerebrospinal fluid*; D051907:Lysosomal Membrane Proteins / Q000134:cerebrospinal fluid*; D008247:Lysosomes / Q000737:chemistry*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000134:cerebrospinal fluid*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000134:cerebrospinal fluid; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010588:Phagosomes / Q000737:chemistry; D033921:Vesicular Transport Proteins / Q000134:cerebrospinal fluid*; D020691:rab GTP-Binding Proteins / Q000134:cerebrospinal fluid*; D020692:rab3 GTP-Binding Proteins / Q000134:cerebrospinal fluid*; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins / Q000134:cerebrospinal fluid; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000418:Albumins; D016229:Amyloid beta-Peptides; D015415:Biomarkers; D002556:Cerebrospinal Fluid Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D020692:rab3 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D016875:tau Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human; C477012:MAP1LC3A protein, human; C075222:amyloid beta-protein (1-42); C093846:early endosome antigen 1; C000716463:rab7 GTP-binding proteins, human